Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes
Authors: Gregory P. Forlenza, Jennifer McVean, Roy W. Beck, Colleen Bauza, Ryan Bailey, Bruce Buckingham, Linda A. DiMeglio, Jennifer L. Sherr, Mark Clements, Anna Neyman, Carmella Evans-Molina, Emily K. Sims, Laurel H. Messer, Laya Ekhlaspour, Ryan McDonough, Michelle Van Name, Diana Rojas, Shannon Beasley, Stephanie DuBose, Craig Kollman, Antoinette Moran, Antoinette Moran, Jennifer McVean, Shannon Beasley, Beth Pappenfus, Anne Street, Brittney Nelson, Janice Leschyshyn, Jane Kennedy, Ihsan Rizky, Gregory Forlenza, Erin Cobry, Laurel Messer, Robert Slover, Paul Wadwa, Lindsey Towers, Angela Karami, Emily Fivekiller, Emily Boranian, Estella Escobar, Emily Jost, Samantha Lange, Cari Berget, Luke Geiser, Mark Clements, Wayne Moore, Ryan McDonough, Emily Paprocki, Kelsee Halpin, Yun Yan, Erica Livingston, Kelsye Howell, Barbara Seuferling, Susan Parish, Stephen Orlich, Rachel Goff, Anna Neyman, Linda DiMeglio, Stephanie Woerner, Carmella Evans-Molina, Emily Sims, Megan Kirchner, Dana Chatila, Bruce Buckingham, Laya Ekhlasour, Lisa Norlander, Eliana Frank, Bailey Suh, Marci Morgan, Ryan Kingman, Liana Hsu, Jennifer Sherr, Kate Weyman, Eileen Tichy, Michelle Van Name, Michelle Brei, Amy Steffen, Lori Carria, Melinda Zgorski, Colleen Bauza, Roy Beck, Ryan Bailey, Craig Kollman, Stephanie DuBose, Diana Rojas, Nicole Cagnina, Nicole Reese, Heidi Strayer, Emma Smith, Sarah Frey, Shachi Vyas, Jonathan Rosen, Sanjoy Dutta, Robert Janicek, Deanna Gabrielson, Liping Yu, Donald Stablein, Georgeanna Klingensmith, Henry Rodrigeuz
Journal: JAMA (2023)

Importance In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, Setting, and Participants This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main Outcomes and Measures The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A 1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, −0.3% [95% CI, −1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and Relevance In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy. Trial Registration ClinicalTrials.gov Identifier: NCT04233034